Over the past two decades, the majority of drug candidates discovered by the pharmaceutical industry have been extremely insoluble in water. Indeed, two out of three compounds selected for development as drug products are very poorly water-soluble. Horspool et al., “Advancing new drug delivery concepts to gain the lead,” Drug Delivery, Vol. 3, pp. 34-46 (2003). Poor water solubility leads to low solubility in gastrointestinal fluids, thereby limiting the dissolution rate of the drug products in the gastrointestinal tract. Accordingly, formulation of such compounds often leads to drug products with incomplete and variable bioavailability and suboptimal clinical efficacy. The bioavailability of these compounds could also be susceptible to food effect.
In recent years, the conversion of drug particles from the micrometer range (microparticles) to the nanometer range (nanoparticles) has emerged as a very attractive approach for enhancing the dissolution rate and the bioavailability of poorly water-soluble drugs. Through particle size reduction to the nanometer range, the surface areas of the drug particles are dramatically increased, thereby resulting in higher dissolution rates and, consequently, higher oral bioavailability. Nanoparticle formulations are usually prepared as liquid nanosuspensions by dispersing nanocrystals in an aqueous media. Liquid nanosuspensions can also be referred to sub-micron colloidal dispersions of drug particles stabilized by surfactants, polymers, or combinations of both.
While nanoparticles are usually produced as liquid nanosuspensions, solid oral dosage forms (e.g., tablets, softgel capsules, hard-shell capsules, and pellets) are the first choice for the development of drug products due to various advantages, such as ease of handling, ease of administration, physical stability and/or patient convenience. To obtain solid, dry drug particles for incorporation into solid oral dosage forms, liquid formulations should be transformed into powder by drying. Generally, the transformation of liquid nanosuspensions into dry solids can be achieved by, for example, tray drying, vacuum drying, lyophilization, spray drying, freeze drying, and spray granulation.
Despite the advantages of solid oral dosage forms, formulating oral solid dosage forms containing nanoparticles has been challenging for formulation scientists for many years. Indeed, among the nanocrystalline products available on the market, only four were developed as solid dosage forms (i.e., Rapamune®, Emend®, Tricor®, and Triglide®), which suggests that there are technical challenges associated with formulating solid oral dosage forms containing nanoparticles. A primary problem in formulating oral solid dosage forms containing nanoparticles is the propensity for the nanoparticles to agglomerate during preparation due to interparticulate interactions and during the drying process of converting the liquid nanosuspension to dry solids. For effective application of nanotechnology to increase dissolution rate and, therefore, bioavailability of poorly water-soluble drugs, it is important that there is no irreversible agglomeration of nanoparticles during drying. Since nanoparticles can spontaneously increase in particle size due to agglomeration, measures must be taken to stabilize them so as to ensure that the surfaces areas of the drug particles are not decreased resulting in lower dissolution rates. A further problem relates to “redispersibility” of the dry solids. It is important that the drug particles return to their original nanoparticle size when the dry solids are redispersed in aqueous fluids, such as digestive juices, after oral administration. If the drug particles are not able to redisperse into the particle size of the original nanosuspension, they will compromise the dissolution rate once in contact with gastrointestinal fluid. This “redispersibility” is essential in order to attain the expected pharmaceutical performances of the drug products. Similarly, the original nanoparticle size should be restored if the dry solids are resuspended in aqueous media for parenteral administration or other routes of administration.
Typically, these problems regarding agglomeration and redispersibility are addressed through inclusion of a significant amount of excipients in the dosage forms, such as stabilizers, cryoprotectants, lyoprotectants, bulking agents, and dispersing agents. See, e.g., Kim et al. “Effective polymeric dispersants for vacuum, convection, and freeze drying of drug nanosuspensions,” Int'l J. of Pharmaceutics, 397, 218-224 (2010). These excipients stabilize nanoparticles by either electrostatic repulsion or steric stabilization via charged stabilizers or non-ionic surfactants/polymers. Examples of commonly used nanoparticle stabilizers in the art include sugar alcohols, water-soluble polymers, polymeric stabilizers, such as povidones, pluronics, and cellulosics (e.g., HPMC and HPC), and surfactants, such as polysorbate 80, lecithins, cholic acid derivatives, and sodium lauryl sulfate (“SLS”). However, in order to overcome the aforementioned problems, the amount of excipients is usually more than the actual drug content, thereby limiting drug loading and compromising the integrity of the final dosage form. In addition, with regard to redispersibility, sonication may be necessary to reduce the particle size of the dry solids redispersed in aqueous media.
Accordingly, there is currently a need in the state of the art for an oral solid dosage form containing nanoparticles that is produced without the need for a significant amount of excipients that would compromise drug loading. In addition, there is a need for an oral solid dosage form containing nanoparticles that exhibits redispersibility without the need for sonication, since sonication is not a physiological condition.
U.S. Pat. Nos. 5,145,684, 5,518,187, 5,862,999, 5,510,118, 5,336,507, 5,340,564, 5,399,363, 5,494,683, 5,429,824, 5,552,160, 5,560,931, 5,565,188, 5,569,448, 5,571,536, 5,591,456, 5,593,657, 5,622,938, 5,718,388, 5,718,919, 6,045,829, 6,068,858, and 6,153,225 describe methods of preparing nanosuspensions. However, in contrast to the present invention, these publications fail to address the issue of the conversion of the nanosuspensions to dry solids and the subsequent redispersion into nanoparticles.
U.S. Pat. No. 5,518,738 describes the dispersion of nanoparticulate naproxen and PVP (K29/32) in water. Redispersants such as hygroscopic sugar, sodium lauryl sulfate (“SLS”), hydroscopic sugar+SLS, dioctyl sodium sulfosuccinate (“DOSS”) were added to the dispersion individually and dried in the oven to produce solid films. However, these formulations showed extremely poor redispersibility.
U.S. Pat. No. 6,375,986 refers to the problem of redispersibility of solid nanoparticulate formulations to their original particle size and discloses that the combination of at least one polymeric stabilizer (PVP) and surfactant exhibits redispersibiltiy of nanoparticulate compositions upon administration to a mammal. However, the mean particle size of redispersion was still higher than the mean particle size of the original nanosuspension even after one minute of sonication. Accordingly, this publication, in contrast to the present invention, fails to demonstrate redispersion into the particle size of the original nanosuspension.
U.S. Patent Application Publication No. 2008/0138424 describes nanoparticulate fenofibrate formulations containing 5% w/w of drug, 1% w/w of hypromellose, and 0.05% w/w of DOSS, resulting in nanosuspensions having particle size of 139 nm (90%<266 nm) with wet media milling. Redispersibility of spray granulated powders of preferred nanoparticulate fenofibrate compositions comprising hypromellose and DOSS with or without SLS was performed in DI water and particle size of resultant nanosuspensions was reported as 390 nm (D90=418 nm) and 182 nm (D90=260 nm), respectively. However, these spray granulated powders contain sucrose at 1:0.6 and 1:1 (drug:sucrose) ratios, respectively. When a nanoparticulate fenofibrate tablet formulation was formulated, a granulated feed dispersion (GFD) was first prepared by combining the nanoparticulate fenofibrate dispersion with sucrose, SLS, docusate sodium and purified water, The GFD was then sprayed onto lactose monohydrate to get a spray granulated intermediate (SGI), and finally the SGI was mixed with additional excipients like microcrystalline cellulose, crospovidone and magnesium before compression into tablets. This formulation was subjected to assess the effect of food on the bioavailability of a nanoparticulate fenofibrate. The formulation and the manufacturing process, unlike the present invention, were very complex and required large amounts of excipients. Also, redispersibility studies were not reported for tablet formulation. It was noted that “the compositions redisperse such that the effective average particle size of the redispersed fibrate particles is less than about 2 microns”, which merely indicates that the compositions did not redisperse to their original particle sizes.
U.S. Pat. No. 5,302,401 has addressed the issue of agglomeration of nanoparticles during lyophilization and described a composition comprised of nanoparticles having a surface modifier adsorbed on the surface thereof and a cryoprotectant associated therewith to prevent agglomeration during lyophilization. The nanodispersions (containing danazol and 1.5% w/w PVP) having a mean particle size of 250 nm was unable to redisperse into particle size of the original nanosuspension and showed a significant increase in the number of particles above 10 μm in the reconstituted dispersion. The addition of sucrose to the danazol/PVP solution substantially reduced particle size growth during lyophilization compared to the nanosuspension which was lyophilized without sucrose. However, the redispersed system had particle size D10 value of 6368 μm compared to original nanosuspension with D10 value of 1122 μm. When mannitol was incorporated (2% mannitol) instead of sucrose, before lyophilization, the particle size redispersed system was observed as 19196 μm.
U.S. Pat. No. 6,045,829 describes formulations of nanoparticulate HIV protease inhibitors comprising a cellulosic surface stabilizer and a dry film nanoparticulate composition. However, the nanoparticulate formulation is mixed with sugar before drying with a drug to sugar ratio of, preferably, between 5:3 and 14:10.
U.S. Patent Application Publication No. 2011/0064812 A1 describes an oral solid dosage form containing nanoparticles in a solution containing fish gelatin to form a nanosuspension and freeze-drying the nanosuspension. However, sugar (especially mannitol) is incorporated as bulking agent in nanosuspension before freeze drying. In the '812 publication, in vitro and in vivo performances of solid dosage forms produced were attributed to their disintegration times. According to the inventors, “the disintegration time targeted for a product made using the present invention can be manipulated to achieve specific disintegration properties that suit pharmacokinetic needs as well as patient requirements.” However, no data on in vitro-in vivo correlation was provided. There was also no determination of the particle size of material after disintegration of dosage forms, since sonication was used “for analysis of all nanosuspensions and solid dosage form testing.”
WO 2007/062266 A2 describes ganaxolone formulations wherein the volume weighted median diameter (D50) of the particles is from about 50 nm to about 500 nm. The ganaxolone formulations are composed of HPMC, SLS, and sucrose and were dried by rotary evaporation and spray layered onto sucrose or microcrystalline cellulose beads. These dried samples showed agglomeration, as redispersion did not result in the original size and had D50 values in the range of 11-25 micrometers. Further, a minute of sonication did not return D50 to its original value.
U.S. Patent Application Publication No. 2012/0244134 A1 describes a process for preparing an aqueous dispersion using a complex stabilizer having an HLB value of about 10 to about 17. The complex stabilizer is comprised of lecithin and at least one non-phospholipid selected from polysorbate, sugar esters, and polyglycerol fatty acid ester. Only sucrose ester with a long chain fatty acid (sucrose stearate) is used. There is, however, no disclosure or suggestion of using sucrose fatty acid esters as a stabilizer for preventing agglomeration during drying or whether redispersion into original nanosuspension particle size occurred. All particle size analysis was conducted after ultrasonication for 5 minutes.
WO 2012/108631 A2 describes wet milling processes to generate nanoparticles of a water insoluble active ingredient with a certain polymer, an organic or inorganic acid, and, optionally, a surfactant. While sucrose fatty acid esters are included in a list of surfactants, there is no disclosure or suggestion of using sucrose fatty acid esters as nanoparticle stabilizers during the preparation of nanoparticles and also during the drying process.
Li et al. reported preparation of nanosuspensions of a drug, oleanolic acid, by using two sugar esters having long-chain fatty acids, sucrose laurate and sucrose palmitate, as surfactants. “Formulation, biological and pharmacokinetic studies of sucrose ester-stabilized nanosuspensions of oleanolic acid,” Pharm. Res. 28(8):2020-33 (2011). The sugar esters were used either alone or as blends, and the relative ratios of the sugar ester to the drug was very high ranging from 10:1 w/w to 2:1 w/w. An emulsion/solvent evaporation method was used to prepare the nanosuspensions. However, the method was complex and not all the drug converted to nanoparticles. In the last two steps of the process, the suspensions were centrifuged to remove excess undissolved materials, and the supernatant was passed through a 0.22 μm membrane filter to give a visually clear nanosuspension. Since the primary focus of the study was biological and pharmacokinetic evaluation of nanoparticles, the filtered suspensions were used for further studies. Although freeze-drying of the filtered suspensions was mentioned, no redispersibility test of the dried materials was performed, and no data were provided.
By providing for a novel preparation of oral solid dosage forms containing nanoparticles wherein sugar ester derivatives serve as nanoparticle stabilizers, the present invention advances the state of the art.